Heterocyclic alkylaminocyclobutenediones

ABSTRACT

The compounds are 1-amino-2-heterocyclic-alkylaminocyclobut-1-ene-3,4-diones which are histamine H 2  -antagonists.

This is a division of application Ser. No. 705,216 filed July 14, 1976,now U.S. Pat. No. 4,062,863 issued Dec. 13, 1977.

This invention relates to pharmacologically active compounds, topharmaceutical compositions containing these compounds and to methods ofblocking histamine H₂ -receptors by administering these compounds. Thecompounds of the invention can exist as acid addition salts but, forconvenience, reference will be made throughout this specification to theparent compound.

Many physiologically active substances elicit their biological actionsby interaction with specific sites known as receptors. Histamine is sucha substance and has a number of biological actions. Those biologicalactions of histamine which are inhibited by drugs commonly called"antihistamines" of which mepyramine is a typical example, anddiphenhydramine and chloropheniramine are other examples are mediatedthrough histamine H₁ -receptors (Ash and Schild, Brit. J. Pharmac.Chemother, 27, 427, (1966)). However, other of the biological actions ofhistamine are not inhibited by "antihistamines" and actions of this typewhich are inhibited by a compound described by Black et. al. (Nature,236, 385 (1972)) and called burimamide are medicated through receptorswhich are defined by Black et. al. as histamine H₂ -receptors. Thushistamine H₂ -receptors may be defined as those histamine receptorswhich are not blocked by mepyramine but are blocked by burimamide.Compounds which block histamine H₂ -receptors are referred to ashistamine H₂ -antagonists.

Blockade of histamine H₂ -receptors is of utility in inhibiting thebiological actions of histamine which are not inhibited by"antihistamines." Histamine H₂ -antagonists are therefore useful, forexample, as inhibitors of gastric acid secretion, as anti-inflammatoryagents and as agents which act on the cardiovascular system, for exampleas inhibitors of the effects of histamine on blood pressure.

In the treatment of certain conditions, for example inflammation and ininhibiting the actions of histamine on blood pressure, a combination ofhistamine H₁ - and H₂ -antagonists is useful.

The compounds of this invention are histamine H₂ -antagonists. Thecompounds may be represented by the following general formula: ##STR1##wherein R is hydrogen, lower alkyl or (CH₂)₂ Z'CH₂ Het': Z and Z' mayeach be sulphur or methylene: and Het and Het' may each be an imidazolering optionally substituted by methyl or bromo, a pyridine ringoptionally substituted by hydroxy, methoxy, chloro or bromo, a thiazolering or an isothiazole ring; or a pharmaceutically acceptable acidaddition salt thereof. By the terms "lower alkyl" and "lower alkoxy" wemean alkyl and alkoxy groups containing from 1 to 4 carbon atoms.

Particularly useful compounds are those wherein Het is:5-methyl-4-imidazolyl, 5-bromo-4-imidazolyl, 3-hydroxy-2-pyridyl,3-methoxy-2-pyridyl, 3-chloro-2-pyridyl, 3-bromo-2-pyridyl, 2-thiazolylor 3-isothiazolyl.

It is preferred that Z should be sulphur and that, when R is (CH₂)₂Z'CH₂ Het', Z' and Het' should be the same as Z and Het respectivelyi.e., so as to form a 1,2-bis compound.

Specific compounds within the scope of the present invention are:

1-amino-2-[2-((5-methyl-4-imidazolyl)methylthio)ethylamino]-cyclobut-1-ene-3,4-dioneand

1-methylamino-2-[2-((5-methyl-4-imidazolyl)methylthio)ethyl-amino]cyclobut-1-ene-3,4-dione.

The compounds of the present invention may be produced by a processwhich commences from an amine of Formula II:

    hetCH.sub.2 Z(CH.sub.2).sub.2 NH.sub.2

FORMULA II

wherein Het and Z have the same significance as in Formula I. This amineis reacted with a compound of the Formula III: ##STR2## wherein A islower alkyl, preferably methyl, and R has the same significance as inFormula I. The compound of Formula III wherein R is hydrogen and A ismethyl is known and wherein R is other than hydrogen may be formed byreaction of the amine RNH₂ with the known "dialkyl squarate" of FormulaIV: ##STR3## wherein A is lower alkyl, preferably methyl.

The compounds of Formula I block histamine H₂ -receptors that is theyinhibit the biological actions of histamine which are not inhibited by"antihistamines" such as mepyramine but are inhibited by burimamide. Forexample, the compounds of this invention have been found to inhibithistamine-stimulated secretion of gastric acid from the lumen-perfusedstomachs of rats anaesthetized with urethane, at doses of from 0.5 to256 micromoles per kilogram intravenously. This procedure is referred toin the above mentioned paper of Ash and Schild. The activity of thesecompounds as histamine H₂ -antagonists is also demonstrated by theirability to inhibit other actions of histamine which, according to theabove mentioned paper of Ash and Schild, are not mediated by histamineH₁ -receptors. For example, they inhibit the actions of histamine on theisolated guinea pig atrium and isolated rat uterus.

The compounds of this invention inhibit the basal secretion of gastricacid and also that simulated by pentagastrin or by food.

In addition, the compounds of this invention show anti-inflammatoryactivity in conventional tests such as the rat paw oedema test, wherethe oedema is induced by an irritant; the rat paw volume is reduced bysubcutaneous injection of doses of about 500 micromoles/Kg of a compoundof Formula I. In a conventional test, such as the measurement of bloodpressure in the anaesthetised rat, the action of the compounds of thisinvention in inhibiting the vasodilator action of histamine can also bedemonstrated. The level of activity of the compounds of this inventionis illustrated by the effective dose producing 50% inhibition of gastricacid secretion in the anaesthetized rat and the dose producing 50%inhibition of histamine-induced tachycardia in the isolated guinea pigatrium.

For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the basic form or in the form of an addition saltwith a pharmaceutically acceptable acid and in association with apharmaceutical carrier therefor. Such addition salts include those withhydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and mayconveniently be formed from the corresponding bases of Formula I bystandard procedures, for example by treating the base with an acid in alower alkanol or by the use of ion exchange resins to form the requiredsalt either directly from the base or from a different addition salt.

Pharmaceutical compositions comprising a pharmaceutical carrier and acompound of Formula I or a pharmaceutically acceptable acid additionsalt thereof and methods of blocking histamine H₂ -receptors whichcomprise administering to an animal a compound of Formula I or apharmaceutically acceptable acid addition salt thereof are also objectsof this invention. The pharmaceutical carrier employed may be, forexample, either a solid or liquid. Exemplary of solid carriers arelactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia,magnesium stearate, stearic acid and the like. Exemplary of liquidcarriers are syrup, peanut oil, olive oil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in power or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 1 g. If a liquid carrier is used, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid contained for example in an ampoule,or an aqueous or nonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the composition in an effectiveamount to block histamine H₂ -receptors. The route of administration maybe internal, for example oral or parenteral, or may be topical.Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 mg to about 250 mg.

The active ingredient will preferably be administred one to six timesper day. The daily dosage regimen will preferably be from about 150 mgto about 1500 mg.

Advantageously the composition will be made up in a dosage formappropriate to the desired mode of administration, for example as atablet, capsule, injectable solution or as a cream or ointment fortopical application.

The invention is illustrated but in no way limited by the followingExamples, in which all temperatures are in ° C.

EXAMPLE 11-Amino-2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-cyclobut-1-ene-3,4-dione.

A mixture of 4-methyl-5-(2-aminoethyl)thiomethyl imidazole (1.47 g) and1-amino-2-methoxycyclobutenedione (0.72 g) was heated to 140° withstirring for 25 minutes. After allowing to cool, the resulting glass waspurified on a column of silica gel, eluting with mixtures of chloroformand ethanol. The solid so obtained was recrystallised three times fromethanol to afford the title compound, m.p. 219° decomp., (0.23 g).

Found: C, 49.1; H, 5.1; N, 20.2; S, 12.5% C₁₁ H₁₄ N₄ O₂ S. requires: C,49.6; H, 5.3; N, 21.0; S, 12.0%).

Reacting with hydrochloric acid gives the hydrochloride salt.

EXAMPLE 21-Methylamino-2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]cyclobut-1-ene-3,4-dione

(i) Into an ethereal solution of dimethyl squarate (5.58 g) was passedmethylamine gas, and the mixture was stirred for 30 minutes at roomtemperature. The precipitated solid was filtered off and dried, andrecrystallised from methyl ethyl ketone to give1-methylamino-2-methoxycyclobutenedione (2.40 g), m.p. 177°-178°.

(Found: C, 51.3; H, 5.0; N, 9.7% C₆ H₇ NO₃. requires: C, 51.1; H, 5.0;N, 9.9%).

(ii) A mixture of 1-methylamino-2-methoxycyclobutenedione (1.20 g) and4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (1.95 g) was heated to170° with stirring for 40 minutes. After allowing to cool, the resultingglass was purified on a column of silica gel, eluting with mixtures ofchloroform and ethanol. The solid so obtained was recrystallised twicefrom ethanol to give the title compound m.p. 207.5°-208.5°, (0.19 g).

Found: C, 51.2; H, 5.9; N, 19.7; S, 11.4% C₁₂ H₁₆ N₄ O₂ S. requires: C,51.4; H, 5.8; N, 20.0; S, 11.4%).

Reacting with maleic acid in ethanol gives the maleate salt.

EXAMPLE 3

When in the procedure of Example 2(i),4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole is reacted with dimethylsquarate, the product is1-methoxy-2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]cyclobut-1-ene-3,4-dioneand when it is further reacted according to the procedure of Example2(ii), the product is1,2-bis-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]cyclobut-1-ene-3,4-dione.Reacting with hydrobromic acid gives the hydrobromide salt.

EXAMPLE 4

Reaction of 1-amino-2-methoxycyclobut-1-ene-3,4-dione according to theprocedure of Example 1 with the following amines:

4-bromo-5-[(2-aminoethyl)thiomethyl]imidazole,

3-methoxy-2-[(2-aminoethyl)thiomethyl]pyridine,

3-hydroxy-2-[(2-aminoethyl)thiomethyl]pyridine,

3-chloro-2-[(2-aminoethyl)thiomethyl]pyridine,

3-bromo-2-[(2-aminoethyl)thiomethyl]pyridine,

2-[(2-aminoethyl)thiomethyl]thiazole,

3-[(2-aminoethyl)thiomethyl]isothiazole and

4-(4-aminobutyl)imidazole

yields the following compounds respectively:

1-amino-2-[2-(4-bromo-5-imidazolylmethylthio)ethylamino]-cyclobut-1-ene-3,4-dione,

1-amino-2-[2-(3-methoxy-2-pyridylmethylthio)ethylamino]-cyclobut-1-ene-3,4-dione,

1-amino-2-[2-(3-hydroxy-2-pyridylmethylthio)ethylamino]-cyclobut-1-ene-3,4-dione,

1-amino-2-[2-(3-chloro-2-pyridylmethylthio)ethylamino]-cyclobut-1-ene-3,4-dione,

1-amino-2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-cyclobut-1-ene-3,4-dione,

1-amino-2-[2-(2-thiazolylmethylthio)ethylamino]-cyclobut-1-ene-3,4-dione,

1-amino-2-[2-(3-isothiazolylmethylthio)ethylamino]-cyclobut-1-ene-3,4-dioneand

1-amino-2-[4-(4-imidazolyl)butylamino]cyclobut-1-ene-3,4-dione.

EXAMPLE 5

When, in the procedure of Example 4,1-methoxy-2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]cyclobut-1-ene-3,4-dioneis used in place of 1-amino-2-methoxycyclobut-1-ene-3,4-dione theproducts are respectively:

1-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-[2-(4-bromo-5-imidazolylmethylthio)ethylamino]cyclobut-1-ene-3,4-dione,

1-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-[2-(3-methoxy-2-pyridylmethylthio)ethylamino]cyclobut-1-ene-3,4-dione,

1-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-[2-(3-hydroxy-2-pyridylmethylthio)ethylamino]cyclobut-1-ene-3,4-dione,

1-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-[2-(3-chloro-2-pyridylmethylthio)ethylamino]cyclobut-1-ene-3,4-dione,

1-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]cyclobut-1-ene-3,4-dione,

1-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-[2-(2-thiazolylmethylthio)ethylamino]cyclobut-1-ene-3,4-dione,

1-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-[2-(3-isothiazolylmethylthio)ethylamino]cyclobut-1-ene-3,4-dioneand

1-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-[4-(4-imidazolylbutylamino]cyclobut-1-ene-3,4-dione.

EXAMPLE 6

    ______________________________________                                        Ingredients             Amount                                                ______________________________________                                        1-Amino-2-[2-((4-methyl-5-imidazolyl)-                                        methylthio)ethylamino]cyclobut-1-ene-                                         3,4-dione               200 mg                                                Sucrose                 70 mg                                                 Starch                  25 mg                                                 Talc                     5 mg                                                 Stearic Acid             2 mg                                                 ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 7

    ______________________________________                                        Ingredients              Amount                                               ______________________________________                                        1-Methylamino-2-[2-((4-methyl-5-imidazolyl)-                                  methylthio)ethylamino]cyclobut-1-ene-3,-                                      4-dione                  200 mg                                               Lactose                  100 mg                                               ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

What is claimed is:
 1. A compound of the formula: ##STR4## wherein R ishydrogen, lower alkyl or (CH₂)₂ Z'CH₂ Het'; Z and Z' may each be sulphuror methylene; and Het is a pyridine ring optionally substituted byhydroxy, methoxy, chloro or bromo Het' is a pyridine ring optionallysubstituted by hydroxy, methoxy, chloro or bromo, a thiazole ring or anisothiazole ring or Het' may be an imidazole ring optionally substitutedby methyl or bromo; or a pharmaceutically acceptable acid addition saltthereof.
 2. A compound according to claim 1 wherein Het' is5-methyl-4-imidazolyl, 5-bromo-4-imidazolyl, 3-hydroxy-2-pyridyl,3-methoxy-2-pyridyl, 3-chloro-2-pyridyl, 3-bromo-2-pyridyl, 2-thiazolylor 3-isothiazolyl.
 3. A compound according to claim 1 wherein Z issulphur.
 4. A compound according to claim 1 wherein R is (CH₂)₂ Z'CH₂Het' and Z' and Het' are the same as Z and Het respectively.
 5. Apharmaceutical composition to block histamine H₂ -receptors comprising apharmaceutical carrier and, in an effective amount to block saidreceptors, a compound of claim
 1. 6. A method of blocking histamine H₂-receptors which comprises administering to an animal in an effectiveamount to block said receptors a compound of claim 1.